Cell growth and differentiation is a highly controlled process which, when uncontrolled, can lead to aberrant cell function, often resulting in a disease state. Protein phosphorylation is one of the main post translational mechanisms used to control cellular function. Protein kinases catalyze the phosphorylation of serine, threonine and tyrosine residues using either ATP or GTP. An analysis of the human genome has revealed that there are predicted to be ˜500 protein kinases (Manning G., Whyte D. B., Martinez R., Hunter T., Sudarsanam S., Science 298, 1912, 2002; Kostich M, English J, Madison V, Gheyas F, Wang L, Qiu P, Greene J, Laz T M., Genome Biol. 3(9), 2002). When phosphorylation regulation by these kinases is lost, a number of diseases may occur, including diabetes, Alzheimer's, inflammation, and cancer (Cohen P., Eur. J. Biochem. 268, 5001-5010, 2001; Cohen P., Nat. Rev. Drug Discovery 1, 309-315, 2002.)
Multiple cellular signals can stimulate growth, differentiation, and apoptosis, and a key mechanism for regulating these processes involves the cell cycle, which controls cell division by regulating passage through the G1, S, G2, and M phases of DNA synthesis and mitosis. Progression through the eukaryotic cell cycle is controlled by the cyclin dependent kinase (CDK) family of kinases. CDKs are primarily serine/threonine kinases and they bind to several different regulatory subunits called cyclins. Different CDK/cyclin heterodimers regulate a variety of processes in the cell cycle, thus, it is believed that CDK-4/cyclin D and CDK-2/cyclin E regulate control through G1 into the onset of the S phase. The down regulation of cyclin D and cyclin E and the up regulation of cyclin A to form heterodimers with CDK-2 and CDK-1 promotes passage through the S-phase into G2. Finally, activated complexes of CDK-1 (Cdc2)/cyclin B and possibly CDK-1 (Cdc2)/cyclin A are thought to promote the transition from G2 into the M-phase (reviewed by Murray A., Cell 116, 221-234, 2004). Some of the known substrates for the CDKs are the tumor suppressor retinoblastoma protein (RB) and related family members p107 and p130 (Grana X., Garriga J., and Mayol X., Oncogene 17, 3365-3383, 1998). Phosphorylation of RB by CDK-4 or CDK-2 induces the release of E2F transcription factors which in turn promote the expression of regulatory proteins to stimulate cell cycle progression and cell growth. In human tumors, the control of the RB function has been observed to be disrupted through mutation of the RB gene, CDK-4 amplification, cyclin D and cyclin E over expression, inactivation of the CDK-4 specific protein inhibitor p16INK4A and a disruption in the level of the CDK inhibitor p27KIP1 (Sherr, C., Roberts J., Genes Dev. 13, 1501-1512, 1999; Hall M., Peters G., Adv. Cancer Res. 68, 67-108, 1996; Stewart T., Wesfall M., Pietenpol J., Trends Pharmacol. Sci. 24, 139-145, 2003). These functional disruptions are believed to contribute to the development of breast, colon, gastric, prostate, nonsmall cell lung, ovarian and other human cancers (Tsihlias J., Kapusta L., Slingerland J., Annu. Rev. Med. 50, 401-423, 1999; Lloyd R., Erickson L., Jin L., Kulig E., Qian X., Cheville J., Scheithauser B., Am. J. Pathol. 154(4), 313-323, 1999).
The fact that uncontrolled regulation of the cell cycle pathway is thought to be a source of human cancers leads one to believe that inhibition of unregulated CDK activity by small molecule inhibitors would be beneficial in the treatment of cancers. A large number of chemical synthesis efforts have been directed toward developing CDK specific ATP competitive inhibitors but only a few molecules have progressed into human clinical trials. These include flavopiridol, roscovitine (CYC-202) and the 2-aminothiazole derivative BMS-387032 (Zhai, S., Senderowicz A., Sausville E., Figg W., Ann. Pharmacother. 36, 905-911, 2002; McClue S., Blake D., Clarke R., Cummings L., Fischer P., MacKenzie M., Stewart K., Wang S., Zhelev N., Zheleva D., Lane D., Int. J. Cancer 102(5), 463-468, 2002; Misra R et. al., J. Med. Chem. 47, 1719-1728, 2004)
There is a need to develop CDK inhibitors for the treatment of human diseases, therefore, it is an objective of this invention to describe compounds that would be useful for the prevention or alteration of these diseases.